Impact of Intradialytic Renal Rehabilitation on the Urea Nitrogen-to-Creatinine Ratio and Its Association With Mortality in Patients on Maintenance Hemodialysis: A Post Hoc Analysis of a Nationwide Multicenter Retrospective Cohort Study (REVEAL-D)

Abstract Background The urea nitrogen-to-creatinine (UN/Cre) ratio has been associated with adverse outcomes in patients undergoing hemodialysis (HD) and may reflect nutritional and catabolic status. We primarily investigated whether intradialytic renal rehabilitation was associated with longitudinal changes in the UN/Cre ratio and additionally examined its prognostic significance and associations with clinical parameters. Methods This was a post hoc analysis of the REVEAL-D retrospective study, a nationwide multicenter cohort in Japan of patients undergoing maintenance HD. The UN/Cre ratio and intradialytic renal rehabilitation status were assessed annually from 2021 to 2024. Linear mixed-effects models were used to evaluate longitudinal changes in the log-transformed UN/Cre ratio according to renal rehabilitation status. Associations of the baseline UN/Cre ratio with all-cause mortality and hospitalization were assessed using multivariable Cox proportional hazards models, and its associations with clinical parameters using multivariable linear regression analysis. Results A total of 695 patients were included; 224 (32%) were receiving renal rehabilitation at baseline. The interaction between renal rehabilitation and study period was not significantly associated with longitudinal changes in the log-transformed UN/Cre ratio, whether rehabilitation status was defined at baseline or treated as a time-varying variable. During a median follow-up of 36 months, 142 patients (20%) died. A higher log-transformed UN/Cre ratio was independently associated with all-cause mortality after full adjustment, including renal rehabilitation status and clinical frailty (hazard ratio, 1.82; 95% confidence interval, 1.02–3.24; P = 0.04), but not with all-cause hospitalization. Higher UN/Cre ratios were also associated with older age, female sex, greater frailty, diabetes mellitus, lower systolic blood pressure, lower albumin and hemoglobin levels, and higher log-transformed C-reactive protein levels. Of the factors independently associated with a higher UN/Cre ratio, hemoglobin level was the only potentially modifiable factor. Conclusions In this Japanese cohort of patients undergoing maintenance HD, intradialytic renal rehabilitation was not associated with longitudinal changes in the UN/Cre ratio. Although a higher UN/Cre ratio was independently associated with all-cause mortality and may reflect the complex interplay of nutritional, inflammatory, and other physiological factors, its clinical utility as a modifiable treatment target remains uncertain.